PROJECT SUMMARY ABSTRACT for The 5th International RASopathies Symposium The 5th International RASopathies Symposium will be held July 28-30, 2017 at the Renaissance Orlando Hotel. The meeting chairs are Katherine A. Rauen, MD, PhD, from the University of California, Davis and Frank McCormick, PhD, FRS, from the National Cancer Institute. Leaders of the RASopathy Network, Lisa Schoyer, MFA (PI), Lisa Schill, BS (Co-I), and Beth Stronach, PhD (Co-I) are parent advocates and will help organize and manage meeting logistics. The symposium will overlap with the Costello Syndrome Family Network conference and provide programming relevant to families with other RASopathies (see below). The Ras/mitogen activated protein kinase (MAPK) pathway is an important biologic pathway with broad developmental impact. This signaling pathway plays an essential role in the regulation of cell growth, differentiation, senescence, and apoptosis, all of which have been studied in the context of cancer. This pathway is also critical to normal development as Ras/MAPK pathway dysregulation has profound deleterious effects on both embryonic and later stages of development. The RASopathies are a group of medical genetic syndromes that are caused by germline mutations in genes that encode components, both positive and negative regulators, of the Ras/MAPK pathway. These syndromes, which share many overlapping phenotypic characteristics, include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), NS with multiple lentigines (NSML), Legius syndrome, Costello syndrome (CS), cardio-facio- cutaneous syndrome (CFC), capillary malformation-arteriovenous malformation syndrome (CM-AVM), and autosomal dominant intellectual disability type 5. Together, the RASopathies represent a common group of developmental malformation syndromes affecting more than 1 in 1000 individuals. Hence, they offer a novel window of opportunity to investigate the role of the Ras pathway in human development and oncogenesis. RASopathies are caused by several pathogenetic mechanisms that alter the normal function and regulation of the MAPK pathway. Although these mechanisms are diverse, the common underlying biochemical phenotype shared by all the RASopathies is Ras/MAPK pathway dysregulation. This symposium will focus on the germline mechanisms of Ras/MAPK activation and dysfunction. It is to be a forum for researchers, clinicians, trainees, and affected families to share and discuss basic science and clinical issues to set forth a framework for future research, translational applications directed towards therapy, and best clinical practices for Ras/MAPK pathway syndromes. Though this is the fifth such meeting, the inclusion of many stakeholders in the scheme of developing effective therapies is integral to future scientific breakthroughs.